Twin studies have provided decisive evidence for the hereditary nature of body weight regulation, demonstrating that individual differences in tendencies to gain weight can be explained by an interaction between genotype and nutrition. The exact mechanisms that connect genes to weight gain remain unknown, but they are crucial to understanding the pathogenesis of common obesity. Our goal is to identify central nervous system (CNS) mechanisms that contribute to genetic susceptibility to weight gain in the modern food environment. To this end, we will use neuroimaging to assess potential CNS mechanisms, and twin research methods to establish the mechanisms' genetic basis and their link to susceptibility to obesity. We, and others, have used functional magnetic resonance imaging (fMRI) to demonstrate that visual images of food powerfully stimulate brain areas active in regulating energy homeostasis, reward, and cognitive control of behavior. Whether these neural responses have a genetic basis is uncertain. Prior research suggests that obese persons have alterations in brain response to food cues that might promote overeating. Both human and animal studies also suggest that satiety is impaired in obese persons. To investigate these theories, we will use fMRI with visual food cues, augmented by functional connectivity analyses that examine brain function at a systems level. We will thereby provide new data on the extent to which observed differences in brain response to food cues among obese persons, as well as impaired satiety, represent genetic predispositions vs. potentially modifiable environmentally-mediated or acquired traits. We will implement our established fMRI protocol for measuring brain response to visual food cues in 2 twin samples recruited from the University of Washington Twin Registry. A random sample of 20 monozygotic pairs will allow us to test whether inherited factors can account for individual differences in brain response. We will also assemble a targeted sample of 21 monozygotic and 21 same-sex dizygotic twin pairs discordant for body mass index to: 1) determine whether body fat mass is associated with brain response to visual food cues and establish whether the association is mediated by inherited or acquired factors, and 2) determine whether impaired satiety is associated with body fat mass and, if so, whether impairments derive from peripheral or central abnormalities in satiety processing. All twins will be genotyped for variant alleles in the fat mass and obesity-associated (FTO) gene, one of the most common obesity susceptibility genes, in order to compare brain response to visual food cues in twins with and without FTO gene variants. This proposal has the potential to advance scientific knowledge of the brain's regulation of appetite and satiety. It will also provide insights into the CNS mechanisms by which inherited factors might predispose individuals to obesity, thereby guiding future research and targeting interventions for those at highest risk.